chr16-15724286-C-T
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The ENST00000300036.6(MYH11):c.4240G>A(p.Ala1414Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 1,614,200 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1414V) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 3 hom. )
Consequence
MYH11
ENST00000300036.6 missense
ENST00000300036.6 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 2.73
Genes affected
MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]
NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH11. . Gene score misZ 1.4389 (greater than the threshold 3.09). Trascript score misZ 3.4142 (greater than threshold 3.09). GenCC has associacion of gene with aortic aneurysm, familial thoracic 4, visceral myopathy 2, familial thoracic aortic aneurysm and aortic dissection, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, megacystis-microcolon-intestinal hypoperistalsis syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.05219561).
BP6
Variant 16-15724286-C-T is Benign according to our data. Variant chr16-15724286-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201073.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=4, Likely_benign=4}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000538 (82/152320) while in subpopulation NFE AF= 0.000911 (62/68022). AF 95% confidence interval is 0.000729. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYH11 | NM_002474.3 | c.4240G>A | p.Ala1414Thr | missense_variant | 31/41 | ENST00000300036.6 | NP_002465.1 | |
| MYH11 | NM_001040113.2 | c.4261G>A | p.Ala1421Thr | missense_variant | 32/43 | ENST00000452625.7 | NP_001035202.1 | |
| NDE1 | NM_017668.3 | c.*35C>T | 3_prime_UTR_variant | 9/9 | ENST00000396354.6 | NP_060138.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYH11 | ENST00000300036.6 | c.4240G>A | p.Ala1414Thr | missense_variant | 31/41 | 1 | NM_002474.3 | ENSP00000300036 | P3 | |
| MYH11 | ENST00000452625.7 | c.4261G>A | p.Ala1421Thr | missense_variant | 32/43 | 1 | NM_001040113.2 | ENSP00000407821 | ||
| NDE1 | ENST00000396354.6 | c.*35C>T | 3_prime_UTR_variant | 9/9 | 1 | NM_017668.3 | ENSP00000379642 | P1 |
Frequencies
GnomAD3 genomes 0.000539 AC: 82AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000457 AC: 115AN: 251476Hom.: 0 AF XY: 0.000434 AC XY: 59AN XY: 135914
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GnomAD4 exome AF: 0.00102 AC: 1484AN: 1461880Hom.: 3 Cov.: 72 AF XY: 0.000935 AC XY: 680AN XY: 727236
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GnomAD4 genome 0.000538 AC: 82AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74488
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 18, 2023 | The MYH11 c.4240G>A p.Ala1414Thr variant (rs112467954), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 201073). This variant is found in the general population with an overall allele frequency of 0.04% (125/282,870 alleles) in the Genome Aggregation Database. The Alanine at codon 1414 is moderately conserved, but computational analyses predict that this variant is uncertain (REVEL: 0.296). Due to limited information, the clinical significance of the MYH11 p.Ala1414Thr variant is uncertain at this time. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2018 | Although the A1414T variant of uncertain significance in the MYH11 gene has not been published as a pathogenic variant or as a benign variant to our knowledge, this variant has been identified, both independently and/or in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The A1414T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, this variant is observed in 94/126710 (0.07%) European (non-Finnish) alleles and 20/34420 (0.06%) Latino alleles in large population cohorts (Lek et al., 2016). - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | MYH11: BP4 - |
Familial thoracic aortic aneurysm and aortic dissection Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 13, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 14, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Lissencephaly 4 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Aortic aneurysm, familial thoracic 4 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 09, 2022 | Variant summary: MYH11 c.4261G>A (p.Ala1421Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 282870 control chromosomes (gnomAD), predominantly at a frequency of 0.00074 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 592 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.4261G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance and four as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
MYH11-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 02, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Connective tissue disorder Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;.;M;M
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;N
REVEL
Uncertain
Sift
Benign
T;T;.;T
Sift4G
Benign
T;T;T;T
Polyphen
0.017
.;.;.;B
Vest4
MVP
MPC
ClinPred
T
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at